Entry of the human immunodeficiency virus (HIV) into target cells involves[unreadable] initial binding of virus to the cellular receptor, the CD4 glycoprotein,[unreadable] and subsequent fusion of viral and cellular membranes and release of the[unreadable] viral core into the cytoplasm. Both binding and fusion steps are[unreadable] mediated by the viral envelope glycoprotein, which in HIV consists of two[unreadable] non-covalently-associated subunits, gp120 and gp41. The high affinity[unreadable] binding of virus to receptor is mediated by gp120, whereas fusion is[unreadable] thought to involve a hydrophobic "fusion peptide" at the amino terminus[unreadable] of the transmembrane subunit, gp41. Details of the interaction between[unreadable] gp120 and CD4 have received considerable attention, since agents that[unreadable] block this binding prevent initiation of the viral life cycle. Little[unreadable] is known, however, of post-binding events that result in membrane fusion.[unreadable] There is mounting evidence that the binding and fusion steps in HIV entry[unreadable] can be uncoupled. There are numerous examples of CD4+ cells (murine[unreadable] cells, for example) that are resistant to infection even though the virus[unreadable] can bind to receptor. This phenomenon appears to involve a block before[unreadable] membrane fusion. Specific sequences within a region of gp120 (the V3[unreadable] domain) not involved in binding to CD4 have been shown to determine[unreadable] cellular tropism and initiation of the fusion step. These findings[unreadable] suggest that cellular factors other than CD4 need to be matched to[unreadable] specific sequences int he envelope glycoprotein for fusion to proceed.[unreadable] Recent results from several laboratories indicate that the defect in[unreadable] fusion can be complemented in trans in heterokaryons. This indicates[unreadable] that resistance to infection is due to the absence of one or more[unreadable] cellular factors, other than CD4, involved in HIV entry. The proposed[unreadable] experiments will seek to identify novel host cell factors involved in HIV[unreadable] entry using both genetic and immunological approaches. Somatic cell[unreadable] hybrids will be used to identify human chromosomes encoding genes[unreadable] required for viral entry; mutant CD4+ cell lines that have lost the[unreadable] capacity to be infected with HIV will be identified and characterized;[unreadable] and gene transfer approaches will be developed to isolate gene encoding[unreadable] the relevant host factors required for HIV entry. In an alternative[unreadable] approach, screening assays will be developed to identify new monoclonal[unreadable] antibodies that block HIV entry by interfering with cellular factors[unreadable] other than CD4. The results of these studies should provide insight into[unreadable] the complex mechanism of HIV entry and may suggest novel approaches for[unreadable] interfering with the earliest step in the HIV life cycle.[unreadable]